Intersection of health and social disparities among the onset and

treatment of Triple Negative Breast Cancer: An interdisciplinary

comparison of Caucasian American and African American
Women’s experiences.

Sophia Sarai Quiroz Rea

The University of California at Los Angeles

Honors Collegium Senior Capstone Project
June 09, 2022
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Introduction
Triple negative breast cancer (TNBC) occurs in 10-15% of breast cancer (BC) patients at

diagnosis, yet it accounts for almost half of all BC related deaths. Although initially responsive to

some cytotoxic chemotherapies, TNBCs tend to relapse early and metastasize, leading to poor

survival. Women of African descent (AW) are twice more likely than Caucasian women of

European Descent (CW) to be diagnosed with TNBC and 41% more likely to die of this disease.

As compared to CW, AW present with the disease at earlier onset and more advanced stage at

diagnosis. Evidence indicates that such TNBC health disparities are due in part to both

non-biological socio-environmental factors and biological factors. TNBCs lack expression of

estrogen receptor (ER), progesterone receptor (PR) and HER2 over-expression and cannot be

treated with commonly used targeted therapies.

The objective of this paper is to study the interdisciplinary interaction between biological and

non-biological factors that exist in Triple Negative Breast Cancer among African and Caucasian

women's response to treatment and survival. I will correlate how multiple social factors and

increased BC risk factors influence outcomes in women of African ancestry compared to women

of European ancestry.

Research will include the studying of combination treatments to target different metabolic

signaling pathways to inhibit breast cancer growth and metastasis using human TNBC cell lines

that are generated from Caucasian and African women in the laboratory. I will compare each cell

line’s treatment responses to Metformin – a drug commonly used to treat diabetes with

demonstrated anticancer properties. It will be determined if there are any inherited racial
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differences that affect response to Metformin and newly designed Metformin analogues. I will try

to correlate biological differences that influence breast cancer response to treatment among AW

and CW, while also considering the social factors that contribute to this significant health

disparity, particularly obesity and diabetes incidence among other social factors that may impact

life outcomes.

Background & Literature Review

What is triple negative breast cancer?

Breast cancer is one of the most prevalent cancers globally. In 2020, nearly 2.3 million women

were diagnosed with some form of breast cancer. The true rate of cases and deaths could be

higher, as this number could be an underestimation of the women affected by breast cancer, due

to under-reporting and cases that have gone undiagnosed. There are several subtypes of breast

cancer; categorized by the types of hormone receptors (HR) or other proteins involved in the

development of the cancer. There are Luminal A or HR+/HER2- (HR-positive/HER2-negative)

subtypes, Luminal B or HR+/HER2+ (HR-positive/HER2-positive), and Triple-negative or

HR-/HER2- (HR/HER2-negative) subtypes2. Triple Negative Breast Cancer is a rare form of this

disease, accounting for 10-15 percent of all breast cancer diagnoses. Triple Negative Breast

Cancer (TNBC) is characterized by its ​lack of expression of Estrogen hormone receptors (ER-),

Progesterone hormone receptors (PR-), and does not overexpress Human Epithelial Growth

Factor (HER2-) genes. Triple Negative Breast Cancer is considered a rare diagnosis, but

accounts for nearly 50 percent of all breast cancer related deaths1.

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Table 1 Subtypes of Breast Cancer as indicated by the presence or absence of Estrogen or

Progesterone hormone receptors and the expression of the Human Epithelial Growth
Factor (HER2) gene. Luminal A and B subtypes are HR+HER2-, while the HER2+ subtype is
HR-HER2+, and Basal-like, or TNBC, is triple negative (ER-PR-HER2-).

Current therapies for Breast Cancer

Breast Cancer treatments and therapies have advanced through previous research, and multiple

forms of treatment are currently available. Several of these treatment options include radiation

therapy, chemotherapy treatment, hormone therapy, biological immunotherapy, and surgery for

nonmetastatic tumors. While shown to be highly effective for other types of hormonal breast

cancers, TNBC does not respond well to hormonal medication treatment that contains estrogen

or progesterone, thus chemotherapy is the primary form of treatment for TNBC patients.

However, the toxic effects of chemotherapy treatment present a less ideal approach for patients’
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overall quality of life and survival rate. In addition, TNBC has shown resistance and relapse to

chemotherapy treatment over time, leading to further metastasis and poor survival rates1.

A newer type of therapy being introduced is CDK 4/6 inhibitor therapy. CDKs, or

Cyclin-Dependent Kinases, are heavily involved in the cell cycle. CDK 4 and CDK 6 are enzyme

complexes essential to cell growth and proliferation, and act as a checkpoint for a specific section

of the cell cycle to progress. The deregulation of the Cyclin Dependent Kinase family is known

to cause disease and cancer in cells as a result of its abnormality2. CDK 4/6 inhibitors are

synthesized compounds that halt the cell signaling pathway initiated from the CDK 4/6 complex,

stopping cell cycle progression and thus proliferation of tumor cells. While these inhibitors can

be effective in preventing further tumor cell growth, the current FDA-approved CDK 4/6

therapies are for HR+ and HER2- breast cancer types, and there are less readily available for

Triple Negative Breast Cancer.

Disparities among TNBC patients

TNBC has a higher prevalence in African American and Hispanic women, and this health

disparity has also been associated with a worse prognosis in women who have Diabetes Mellitus

Type 24. It is known that biological and non-biological factors play a role in the etiology of these

health disparities, and these cancers are linked to health disparities among different social groups.

Figure 1 describes the increased incidence of TNBC among African American Women and their

survival rate in comparison to European American Women2. Graph A depicts higher rates of

TNBC incidence among African American women ages 20-54. Graph B displays the survival

distribution fraction over time among the two groups, which is considerably lower for African
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American women than women of European descent, highlighting the disparities among the two

groups.

Figure 1 Increased incidence of TNBC and poor survival rate among African American
women compared to European American women.
A). The percentage of TNBC incidence among African Americans is higher than European Americans.
B). The Survival Distribution Fraction over time is lower for African Americans than for European
Americans.

Non-Biological Determinant Factors

Comorbid disease: Obesity & Diabetes

There are non-biological factors that affect the incidence and risk of developing TNBC. Obesity,

for example, is becoming a more and more significant part of modern life and has spread quickly

in a short amount of time. Based on the National Health and Nutrition Examination Survey from

2014, the United States observed 35.0% of adult men and 40.4% of adult women were obese, as
 Quiroz 6

measured by Body Mass Index. (Dietze, obesity). There is an increased likeliness for women to

be more obese than men, and this number is seeing a rising trend in the United States.

Obesity is also linked to various social factors that unequally affect minority groups, and presents

a risk factor for developing diabetes mellitus type II. Diabetes mellitus type II is a metabolic

disease that affects millions and has proven to be an increased risk factor for developing breast

cancer. More than 37 million people have been diagnosed with diabetes in the United States,

90-95% of which have type II diabetes6. Type II diabetes is primarily affected by insulin

resistance of the body, resulting in accumulation of glucose levels in the blood. This can result in

several health complications, ranging from the increasing urge to urinate to heart attack or stroke.

Diabetes mellitus type II occurs more commonly in minority groups, primarily African

American, Hispanic, Asian, and Native American 6.

The mechanistic link between diabetes and breast cancer has been linked to three possible

signaling pathways affected: activation of the insulin pathway, activation of the insulin-like

growth factor pathway, and the regulation of sex hormones7. Insulin is a hormone that helps to

regulate blood sugar in the body. The insulin receptor is expressed and stimulated in breast

cancer cell lines, and an overexpression of the receptor can lead to the malignant transformation

of breast epithelial cells7. Hyperinsulinemia, or the increased presence of insulin, can also

increase the metastasis of breast cancer cells by activating the insulin receptor and insulin-like

growth factor pathways8. Previous studies have correlated the high presence of insulin receptors

(IR) and Insulin-like growth factor 1 receptor (IGF-1R) in breast tumors to a worse prognosis and

resistance to therapy8.
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Besides its role in allowing glucose to enter the body’s cells, insulin is also an essential sex

hormone regulator. When there is increased insulin resistance in the body, it can lead to an

increase in androgen synthesis and a decrease in the production of estrogen. This low production

of estrogen can lead to a higher risk of developing cancer in organs that highly express estrogen

and have hormonal receptors such as breast tissue.

Figure 2 Map of diabetes and obesity by county in the United States: 2004, 2009, 2014, and
2019. Content source: Centers for Disease Control & Prevention.

This map shows the incidence of obesity and diabetes over the course of 14 years, as measured by
the CDC. The Blue gradient shading represents the percentage of Obesity per county, while the Red
gradient shading represents the percentage of Diabetes per county. The combined range in purple
represents the percentage of each county diagnosed with both Obesity and Diabetes.
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Because of the connection linking diabetes to breast cancer, and obesity to diabetes, we can

ascertain that there are causes for breast cancer rooted in systemic inequality and social

disparities. About 50% of breast cancer patients with diabetes are likely to result in death and are

at the most significant risk of chemotherapy-related toxicity7. The causes of diabetes are

multifaceted, but lifestyle and social factors have a significant role in its onset. Income

disparities, food deserts and insecurity, and neighborhood and community disparities are all

non-biological social factors that contribute to the onset of obesity and diabetes, which I will

discuss further in the following sections.

Socioeconomic Status
One of the primary barriers to prevention of diabetes mellitus type II and risk factors for breast

cancer development is socioeconomic status and social class. The correlation between poverty

and obesity and subsequent comorbidities can be seen in the overproduction and consumption of

processed food. Processed foods that are calorie-dense and high in carbohydrates are often more

affordable, and a cheaper food alternative for families of low socioeconomic status than many

fresher healthier food options5. This disproportionately affects African Americans, who have on

average made half of the income of white families in a 1:2 ratio, reported as of 20109. This

income and wealth gap can have a negative impact on the metabolic health of African American

women who become more at risk for developing lifestyle diseases that may in turn put them at

higher risk of being diagnosed with breast cancer.

Access to Care
When it comes to disparities in the onset of breast cancer, access to primary care is essential for

prevention and early detection. African American women in the United States overall tend to
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receive less primary care than Caucasian American women. The type of lifestyle, location and

affordability all have an impact on who gets access to care and what kind of care they may have

access to. Access to care can be affected by many factors, including having a regular primary

physician, geographical barriers to accessing care, and type of insurance. Having a regular

primary care provider is linked to a higher utilization of preventative care such as mammography

screenings10. Lack of access to screening, oncology care, and delays in treatment are all

contributing factors to increased TNBC mortality for women of African descent11. Geographical

access to care is another barrier in breast cancer prevention. Because many care facilities are not

located near places where the disadvantaged live, women who live in more disadvantaged remote

areas need to travel further distances and experience longer wait times to receive breast cancer

treatment and screenings10. It is not a secret to physicians that African American women face

more barriers; in an interview3, Tuya Pal, MD, associate director for health disparities, Ingram

professor of cancer research and professor of medicine and pediatrics at Vanderbilt-Ingram

cancer center asserts:

“these women are less likely to be given recommendations for genetic testing
— there is something systemic going on here. ... The hoops that Black women
have to jump through in regard to insurers requiring a genetics professional to
perform an assessment for genetic testing may be what reduces their chances
of receiving genetic testing.”

These factors, combined with the inconvenience of working hours and time and cost for

transportation deter these women from seeking out primary preventative care. Health insurance

coverage is also a limiting factor for African American women. Different experiences with

insurance coverage and service could lead to delays in diagnosis, treatment and care. A delay in

diagnosis could be significant, as more time passes between testing and diagnosis there is more
 Quiroz 10

opportunity for metastatic activity to continue, and prognosis to worsen before being diagnosed.

Of patients surveyed who have private insurance, the diagnostic time delay for African American

women was 55 days, while Caucasian American women experienced a 43 day diagnostic delay

(Danforth). This difference shows the significance of delays in treatment and care, and highlights

both the disparity and need to prioritize and improve primary care and prevention, which could

make a large difference in the experiences for women of African descent.

It is clear that multiple non-biological social factors contribute to the health disparity related to

TNBC. Women of African descent face marginalization and exclusion by social systems that are

failing them. That is not to say, however, that these are the only factors that contribute to TNBC

health disparities. There are biological factors that can influence health outcomes between

European ancestry and African ancestry cell lines.

Biological Determinant Factors

African Ancestry vs. European Ancestry cell lines

Studies about biological differences in the past have yielded conflicting results, but are suggested

to exist in some form among African and European ancestries. The BRCA1 gene is a

tumor-suppressor gene commonly found mutated in Caucasian TNBC patients11. Interestingly,

there are considerably less BRCA1 mutations found in women with TNBC of African descent

than European descent, suggesting that women of African descent experience a different genetic

susceptibility11.
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Biologically inherited racial differences have been observed among human cell lines of African

Ancestry and European Ancestry. Human cell lines are taken from patient samples and used in

research and observation. Some differences among races have been observed in immune

signatures. Breast Cancer Stem Cells (BCSCs) mediate tumor recurrence and metastasis, and are

prevalent in African TNBC tumors (Jiagge). Gene expression of BCSCs in African ancestry can

contribute to treatment resistance, and has been seen to affect those of African ancestry more

than European ancestry.

Table 2 African Ancestry and European Ancestry cell lines used in laboratory research.
This table is a list of different ancestry cell lines used in the research conducted for this study.
All cell lines used are TNBC.

Metabolic Signaling Pathway Targets

The targeting of TNBC treatment has been difficult due to its characteristic of the lack of specific

receptors used in targeted therapy such as antiestrogens or HER2 inhibitors1. Another way that

has been proposed to use as a targeted therapy is through the metabolic vulnerabilities found in

TNBC1. The use of Metformin, a drug therapy commonly used to treat diabetes mellitus type 2,

has proven to have anticancer properties16. With Metformin’s effect on metabolic signaling

pathways, this could pose a new form of targeting TNBC.

 Quiroz 12

One of the metabolic signaling pathways involved is the AMPK/mTOR signaling pathway. The

AMP activated protein Kinase (AMPK) pathway is essential for stimulating catabolic pathways

that increase ATP production. Known as the ‘master regulator of the cell metabolism’, it plays an

essential role in preventing tumor proliferation by blocking m-TOR signaling pathways

(Garban). The mammalian target of rapamycin (mTOR) signaling pathway is involved in cell

growth, proliferation, protein synthesis, autophagy, and transcription, and is dysregulated in

certain diseases and cancers. Metformin increases insulin sensitivity and lowers expression of

gluconeogenic enzymes12, and has been observed to directly stimulate the AMPK pathway in

tumor cells, which in turn suppresses downstream mTOR signaling and tumor growth.

Cyclin Dependent Kinases (CDKs) in the cell cycle are another target from the cell cycle that can

be used to treat TNBC. Cyclin Dependent Kinases are protein kinases or enzymes that require

cyclin proteins to perform duties that are heavily involved in the cell cycle, such as regulating

transcription, mRNA processing, and differentiation of specialized cells in the cell cycle. CDK 4

and CDK 6 are two of many cell-cycle specific kinases and participate in regulation of cell

proliferation. CDK4/6 is a main component involved in the first G1/S transition checkpoint in

the cycle and the target for the mechanism of action of CDK 4/6 inhibitor Trilaciclib.
 Quiroz 13

Research Methods

Metformin and Metformin analogue treatment responses

Metformin is a compound that has been used to treat diabetes mellitus type 2 but has also shown

to have antitumor properties1. In previous studies, Metformin has been shown to induce

autophagy and G1/G0 cell cycle arrest by targeting the AMPK pathway12. Metformin causes an

upregulation of the AMPK pathway and a downregulation of mTOR, and therefore can prevent

protein synthesis and cell proliferation12. However, while proving its modest anti-tumor effects at

high doses, Metformin also exhibits undesirable side effects, which limit its dosing. Thus,

Metformin analogues with more potent effects at lower doses are desirable. In conjunction with

Dr. Michael Jung (Department of Chemistry, UCLA), Dr. Richard Pietras and Dr. Diana Marquez

Garban (Department of Medicine, Division of Hematology-Oncology, UCLA), several of these

Metformin analogues were synthesized and tested in vitro. For this study, Metformin analogue

‘JD006’ was used as the primary analogue, and its treatment response was compared to parental

Metformin on the various cell lines from African and European heritage.
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Figure 3. Mechanism of Action of Metformin on AMPK Signaling Pathway. This figure

shows both the indirect and direct effects of Metformin. Metformin is shown to be involved in
this signaling pathway by activating AMPK and inhibiting mTOR1 signaling, also preventing
further proliferation and migration of tumor cells.

CDK 4/6 Inhibitor Therapy

Another important component in the cell cycle is the retinoblastoma protein (Rb), a tumor

suppressor protein13. CDK 4/6 forms a complex with Cyclin D1, which phosphorylates Rb14.

When Rb is phosphorylated, it can no longer prevent the progression of the cell cycle. In a

cancer cell, this makes it possible to continue proliferating and creating further tumor growth.

The function of CDK 4/6 inhibitors is to prevent phosphorylation of Rb, therefore allowing it to

perform its tumor suppressing function and arrest the cell cycle in the G1 phase to prevent

proliferation of cancer cells14. Trilaciclib is a type of CDK 4/6 inhibitor that has been shown to

reduce myelosuppression in chemotherapy treatment and can improve survival outcomes for
 Quiroz 15

TNBC patients when combined with chemotherapy. Trilaciclib recently received FDA approval

and has been used in clinical settings on patients undergoing chemotherapy.

Figure 4. Cell cycle phases and the regulatory components important in breast cancer
disparities. Cyclins A, B, D, and E, p16/INK4A, the tumor suppressor genes p53 and
RASSF1A, as well as hormones and growth factors have been identified in multiple regulatory
components of the cell cycle in the breast cancer of African American compared with
Caucasian women. The CDK 4/6 complex is located at the G1 phase of the cell cycle.
Content source: Danforth, et al.
 Quiroz 16

Objective: Combination treatments to target metabolic signaling pathways

Previous studies have shown there is a possible synergistic effect with CDK 4/6 inhibitors and

Metformin16. Our objective was to test whether novel metformin analogues with more potent

anticancer activity than parental metformin in combination with Trilaciclib can stop triple

negative breast cancer proliferation and cell growth by suppressing mammalian target of

rapamycin (mTOR) signaling and by targeting metabolic vulnerabilities unique to this breast

cancer subtype. Our specific aim is to determine whether treatment with Trilaciclib, JD006,

Metformin, or a combination of such compounds can prove a more effective treatment response

for Triple Negative Breast Cancer than each treatment alone, and what that could indicate for

treatment response and remission for TNBC patients of African descent. Research methods

included Cell Proliferation Assays with cell lines in culture (Table 2) to determine effects of

parental Metformin, Metformin analogue JD006, and CDK 4/6 inhibitor Trilaciclib on cell

proliferation. Western Blot Assays were used to determine the effects of each of the previously

listed therapies on relevant cell signaling pathways.

Analysis

Results
Metformin analogue JD006 is more effective at inhibiting cell proliferation than parental Metformin.

Figure 5 shows results from cell proliferation assays using TNBC cell lines. Cell proliferation is

expressed as percentage of vehicle treated control. Metformin analogue JD006 was more

effective at reducing cell proliferation in TNBC cell lines from AAW and CW than parental

Metformin in a dose-dependent manner.

 Quiroz 17

Figure 5. Novel analogue JD006 is more effective at reducing cell proliferation of TNBC
cells than parental metformin. Cells were seeded in 96 well plates and treated with
increasing concentrations of JD006 or Metformin (0.125-16 mM). After 72 hours cell
proliferation was assessed with an MTS assay. Results are expressed as percentage of vehicle
treated control. Treatments were done in triplicate and experiments repeated at least 3 times.
African heritage cell lines (HCC1806, MDAMB468, and HCC70) are displayed on the right,
and European heritage cell lines (MDAMB231, BT549, HCC1937, HCC1143) on the left.

Preliminary results show that African heritage cell lines that were initially slow to respond to

Metformin responded significantly more to JD006 when compared to Caucasian European. This
 Quiroz 18

aligns with the previous finding that African heritage cell lines had a greater glycemic response

to Metformin when compared to European Americans 17.

Trilaciclib inhibits TNBC cell proliferation in vitro

TNBC cells were incubated with increasing concentrations of Trilaciclib. Cell proliferation was

estimated after 5 days. Figure 6 shows Trilaciclib significantly inhibits TNBC cell proliferation in

a dose dependent manner in all TNBC cell lines treated.

 Quiroz 19

Figure 6. Trilaciclib inhibits cell proliferation of TNBC cells from AAW and CW. Cells
were seeded in 96 well plates and treated with increasing concentrations of trilaciclib (TRILA)
that range from 0.023 – 3 uM. After 5 days, cell proliferation was assessed with an MTS assay.
Results are expressed as percentage of vehicle treated control. Treatments were done in
triplicate and experiments repeated at least 3 times. African heritage cell lines (HCC1806 and
HCC70) are displayed on the right, and European heritage cell lines (MDAMB231, BT549,
HCC1143) on the left.

JD006 and Trilaciclib activate AMPK and inhibit mTOR downstream signaling pathways

Effects of analogue JD006 and Trilaciclib on AMPK downstream signaling were assessed using

Western Blot analysis. Figure 6 shows results from BT549, MDAMB231, HCC1937, and

HCC70 TNBC cell lines. Combination treatment of Trilaciclib and JD006 was more effective at

inducing activation of AMPK, and inhibition of downstream mTOR protein signaling, evidenced

by a decrease in phosphorylation of protein S6, which is involved in cell growth and regulation.
 Quiroz 20

Figure 7. Effect of Trilaciclib and JD006 treatment on downstream AMPK signaling.

TNBC cells were treated with 0.5 and 1 mM JD006 and 0.2 uM Trilaciclib and combination of
both. After 18 hours cells were lysed and 30 ug of total protein were immuno-probed with
antibodies against proteins shown above. GAPDH was used as loading control.
 Quiroz 21

Discussion
The implications of this research could be significant for improving the outcomes of TNBC

patients, especially African American women as they have an increased incidence and mortality

from this breast cancer subtype. There are currently targeted therapies being used with

HR-positive and HER2 related breast cancers that increase patient survival and overall prognosis.

In addition, it is important to determine if this new combination therapy is effective in vivo.

Development of new targeted therapies for treatment of TNBC are urgently needed. While more

research is needed to fully determine the significance between biological heritable factors among

African versus European heritage women, there are solutions that can be done now to reduce the

disparities in social context. Improving the social disparities that disproportionately affect

African American women can help reduce the inequalities in disease for TNBC. Improving

access to healthcare and preventative care through community programs and resources, actively

increasing access to healthy foods to reduce the size of food deserts, and reducing the wealth and

income gap between Caucasian and African American families can contribute to the overall

improvement of health and wellbeing of disproportionately affected groups. Healthcare providers

and physicians should also be more aware of these disparities, and work with their patient

population to improve such issues. Overall, this project has shown that the experiences of TNBC

diagnosis and treatment is greatly influenced by the overlap of social and biological disparities

present, and how a possible solution to a complex issue could be in an interdisciplinary approach

through social and biological research with the goal to find improved TNBC outcomes for

women of African descent.

 Quiroz 22

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Acknowledgements
I would like to express my very great appreciation to my mentors and Principal Investigators Dr. Diana
Marquez-Garban and Dr. Richard Pietras for their valuable and constructive guidance during the planning and
development of this research work. Their willingness to give their time so generously has been very much
appreciated.

This research was supported/partially supported by the California Breast Cancer Research Program B27IB3869, the
Jonsson Comprehensive Cancer Center and Jonsson Cancer Center Foundation Breast Cancer Award, and
U54CA143931 UCLA Jonsson Cancer Center and Charles Drew University Partnership to Target Cancer Health
Disparities in South Central Los Angeles.

I thank Gabriela Llarena, lab technician, and Diana Marquez Garban, lab administrator, for assistance with cell
proliferation assays and western blots in the lab, and comments that greatly improved this work.

This project was done in accordance with the UCLA College Honors Pilot Program as a senior capstone project for
the cohort of 2022.