Treatment options for individuals with breast cancers are generally determined by the status of certain marker proteins in the tumor tissue. Those breast cancers that express estrogen receptors (ERs) are highly likely to respond to hormonal-based therapies. Conversely, the absence of not only ERs, but progesterone receptors (PRs), is often indicative of estrogen insensitivity. Similarly, expression of human epidermal growth factor type 2 receptor (HER2/neu) renders tumors likely to respond to treatments targeting this receptor. Consequently, those patients assaying negative for ERs, PRs, and HER2, defined as “Triple Negative”, are categorized with breast cancer that are generally more aggressive and harder to treat. However, Triple Negative diagnosis is not fully predictive of therapeutic response, with recent findings pointing toward a subset of tumors which utilize androgen receptors (ARs) in place of ERs and a new category, designated “Quadruple Negative” (ER–, PR–, HER2–, AR–). Thus given that conventional Triple Negative diagnosis is not fully predictive of therapeutic response, novel strategies are necessary to better discern diagnosis and improve therapy selection.
Description of Project:
Dr. Monaco has found that the lipid metabolic enzyme acyl-CoA synthetase 4 (ACSL4) is negatively correlated with expression of ER, PR, HER2, and AR status in human breast tumor samples and cell lines. In a survey of 73 breast cancer cell lines, 87% of lines that express one or more receptor are negative for ACSL4 expression, with increasing negative correlation to ACSL4 when receptors were grouped as Double, Triple or Quadruple Negative cell lines. A meta-analysis of public mRNA expression data comparing expression of ACSL4 in Triple Negative tumor samples to biomarker positive samples yielded similar results. More notably, the laboratory has recently demonstrated that ACSL4 positivity alone may indicate estrogen and androgen insensitivity, even in the presence of those respective receptors. Furthermore, the laboratory has generated data suggesting that expression of ACSL4 in human breast cancers has not only prognostic, but therapeutic value. Beyond a productive target for chemotherapy, depletion of the enzyme has been found to result in a decreased ability for ACSL4-expressing tumor cells to grow, metastasize and invade in a Triple- or Quadruple-Negative manner.
Routine measurement of ACSL4 levels would add another indicator of prognosis that could strengthen the predictive value of traditional ER, PR, and HER2 assays, such as confirmation of triple negative status (i.e. ACSL4+) or non-triple negative status (i.e. ACSL4–). However, ACSL4 has the potential of being a biomarker utilized in decision-making, preventing powerful therapies from inadvertently being ruled out. Potentially, triple negative/ACSL4– status may discern a new class of patients that would be responsive to hormonal-based therapies. Conversely, ACSL4+ status may discern a new class of patients who may be [ER–, PR–, HER2+] or [ER+, PR+, HER2–] that would be unresponsive to the standard regiment of receptor- or hormonal-based therapies, respectively. Furthermore, with ACSL4 expression found to be highly elevated in colon adenocarcinoma and hepatocellular carcinoma, the detection of this enzyme could be an important biological marker and guide treatment for the early onset of these other major disease states.
A provisional patent application covering this novel diagnostic has been filed in the U.S.
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